In vitro analysis of the renal handling of paraquat.

Accumulation of paraquat by mouse renal cortical slices was related to the concentration of paraquat in the medium and the duration of incubation. Paraquat accumulation was depressed by incubation of slices under nitrogen or by addition of metabolic inhibitors. Accumulation of a second organic base, N-methylnicotinamide (NMN), was depressed by a concentration of paraquat which failed to influence accumulation of the organic acid, p-aminohippurate (PAH). The uptake component of NMN accumulation was inhibited by paraquat. The data suggest that paraquat is accumulated by an energy-requiring process and that this accumulation occurs via the organic base transport system. In addition, an apparently toxic effect of paraquat on cortical slice function was observed when the incubation temperature was raised from 25 to 37°C. At this temperature, 10^?3m paraquat depressed not only NMN accumulation but PAH accumulation and slice oxygen consumption as well. Thus, paraquat can be toxic to the function of kidney slices and this effect appears to be temperature-dependent.     

Assessment of mercuric chloride-induced nephrotoxicity by p-aminohippuric acid uptake and the activity of four gluconeogenic enzymes in rat renal cortex.

p-Aminohippurate (PAH) uptake and the activities of four gluconeogenic enzymes were used in vitro as indicators of nephrotoxicity in rats. The purpose was to compare the relative sensitivities of the gluconeogenic enzymes (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase, and glucose-6-phosphatase), measured in renal cortical homogenates, and PAH uptake, measured in renal cortical slices, following ip treatment with mercuric chloride (HgCl₂). The morphologic aspects of the nephrotoxicity produced by HgCl₂ were also evaluated. A time study (30 days) following administration of 2 mg/kg of HgCl₂ showed that PAH uptake was more sensitive to HgCl₂ than the activities of the four gluconeogenic enzymes. The greatest inhibitory effect was noted on Day 6 and an increase toward normal was seen from Day 7. A dose-response study undertaken 6 days after HgCl₂ showed that 1 mg/kg caused significant decreases in the activities of fructose-1,6-diphosphatase and pyruvate carboxylase. However, PAH uptake was significantly reduced at 0.5 mg/kg; with this dosage no morphologic renal alterations were observed. PAH uptake was found to be more sensitive for detecting HgCl₂-induced nephrotoxicity than were the activities of the four gluconeogenic enzymes, with fructose-1,6-diphosphatase being the most sensitive of the four enzymes.     

The effect of depletion of nonprotein sulfhydryls by diethyl maleate plus buthionine sulfoximine on renal uptake of mercury in the rat

Rats pretreated with diethyl maleate (DEM, 3.37 mmol/kg, ip) and buthionine sulfoximine (BSO, 0.45 mmol/kg, ip) and subsequently given mercuric chloride (HgCl2, 0.014 mmol/kg, sc) had a significantly greater mortality rate over the 24 hr after injection than rats given only HgCl2 or HgCl2 following either DEM or BSO alone. Depletion of nonprotein sulfhydryls (NPSH) in the kidney significantly decreased mercury uptake in that organ. A similar effect was not seen in the liver despite marked depletion of NPSH. Similarly, there was a tendency for less in vitro mercury accumulation in renal cortical slices from rats made glutathione deficient by DEM + BSO compared to control, or rats made glutathione deficient by DEM or BSO alone. Depletion of nonprotein sulfhydryls by the combination of the depleting agents diethyl maleate plus buthionine sulfoximine (DEM + BSO) had a greater effect to alter organic ion accumulation in renal cortical slices than the agents alone. The higher mortality produced by mercuric chloride after DEM + BSO pretreatment may have been due to an increased availability of mercury in lethal concentrations at other organ sites. These data suggest the possible importance of NPSH in renal mercuric ion accumulation, but not in the liver.     

The acute toxic effects of paraquat and diquat on the rat kidney.

The bipyridyls, paraquat and diquat, cause mild renal tubular damage in the rat. A marked diuresis, albuminuria, glucosuria, and an increased plasma urea concentration occurred 6–24 hr after paraquat (680, po, or 108 μmol/kg, sc) and an increased urinary excretion of N-acetyl-β-d-glucosaminidase occurred 6–24 hr after paraquat (680 μmol/kg, po). Diquat (680 μmol/kg, po) produced proteinuria and glucosuria 6–24 hr after dosing. Histological examination of the kidneys showed there was mild hydropic degeneration of the proximal convoluted tubules. Mercuric chloride (HgCl₂), a nephrotoxic agent, was used as a positive control in these studies dosed at 7.4 μmol/kg, sc, and produced marked tubular necrosis. Biochemical studies showed that both paraquat and diquat decrease N′-methylnicotinamide (NMN) but not p-aminohippurate (PAH) accumulation by renal cortical slices when added in vitro, suggesting competition for the base transport system. However, no decrease in NMN or PAH accumulation was seen in renal cortical slices from rats treated with paraquat or diquat. Both bipyridyls stimulated pentose phosphate pathway and inhibited fatty acid synthesis when added in vitro to renal cortical slices. However, neither of these parameters were affected in renal cortical slices prepared from rats treated with paraquat or diquat. We conclude that both bipyridyls cause renal tubular damage but this damage is mild compared with that seen after HgCl₂. And that biochemical indicators of paraquat damage in the lung are not altered in renal cortical slices from bipyridyl-treated rats. These minimal changes observed using histological and biochemical techniques contrast sharply with the effects these compounds have on renal excretory function.     

Functional nephrotoxicity of gentamicin in the rat

Gentamicin sulfate (GM), 100 mg/kg, was administered once daily for up to 4 days to adult male rats and was found to concentrate in cortical regions of the kidney. Uptake of the organic base N-methylnicotinamide (NMN) by rental cortical slices was reduced by GM treatment, whereas uptake of the organic acid p-aminohippurate (PAH), the sugar analog α-methyl-d-glucopyranoside (AMG), and the amino acid analog α-aminoisobutyrate (AIB) were unaffected. Gentamicin reduced sulfate renal slice formation of glucose and ammonia and the rate of slice respiration. In addition, GM increased urinary excretion of glucose and β-d-galactosidase (β-d-Gal), a proximal tubular cytoplasmic enzyme. These results have led to the hypothesis that GM is a mitochondrial toxin which exerts deleterious effects specifically on the kidney because of selective uptake in this organ.     

Enhancement of renal organic base accumulated by potassium dichromate.

N-Methylnicotinamide (NMN) accumulation by renal cortical slices from potassium dichromate-treated rats was not different from control at 30 min of incubation, but was substantially higher when the incubation was continued for 60 min or longer. Intravenous injection of NMN resulted in significantly higher cortex/serum concentration ratios when rats were treated 24 hr earlier with potassium dichromate. Incubation of renal cortical slices under N₂ or at O°C reduced NMN slice-medium ratios to about 1; reincubation under normal conditions returned the slice/medium ratios to normal values in controls but not in dichromate-treated animals. Replacement of drinking water with saline for 5 wk reduced both the dichromate-induced nephrotoxicity and the enhanced uptake of NMN by kidney slices. Concomitant treatment with dimercaprol and dichromate did not reduce dichromate-induced toxicity or enhancement of NMN slice accumulation. Chromium chloride elicited neither nephrotoxicity nor stimulation of NMN uptake. The enhancement of renal NMN accumulation or retention by potassium dichromate appears to be associated with the nephrotoxicity produced by this compound.     

Furosemide accumulation by renal tissue.

Furosemide accumulation by rabbit kidney cortical slices increased with incubation time, reaching a plateau by 60–90 min. Furosemide uptake by kidney slices from rabbits, dogs, mice and rats was inhibited by dinitrophenol, ouabain and probenecid, and was decreased by incubation at 0°, anoxia or the use of sodium-free medium. Furosemide slice/medium ratios decreased with increasing concentration of furosemide in the incubation medium. Addition of furosemide to medium containing rat kidney slices and either p-aminohippurate (PAH) or N-methylnicotinamide (NMN) produced a dose-related inhibition of PAH, but not NMN, accumulation. It is concluded that furosemide is actively transported by the renal organic anion transport system.     

Renal and hepatic microsomal enzyme stimulation and renal function following three months of dietary exposure to polybrominated biphenyls.

Polybrominated biphenyls (PBB) stimulate microsomal enzyme activity and produce a variety of toxic manifestations, including renal and hepatic histopathological changes. Therefore, it was of interest to determine the effect of chronic exposure to PBB on renal and hepatic microsomal enzyme stimulation and renal function. Adult Sprague-Dawley rats were fed diets containing 0 or 100 ppm of PBB for 3 months. Treatment with PBB retarded weight gain and increased the liver to body weight ratio but did not alter kidney to body weight ratio. Biphenyl-4-hydroxylase (BP-4-OH) and biphenyl-2-hydroxylase (BP-2-OH) activities were elevated in the kidney and liver following treatment with PBB. Exposure to PBB increased aryl hydrocarbon hydroxylase (AHH) activity in the kidney and liver. Epoxide hydratase (EH) activity was increased in the liver but decreased in the kidney following exposure to PBB. A three-month exposure to PBB had no effect on blood urea nitrogen, the clearance of inulin, p-aminohippurate (PAH), or fractional sodium excretion. Similarly, the in vitro accumulation of PAH and N-methylnicotinamide (NMN) in thin renal cortical slices and ammoniagenesis and gluconeogenesis in renal cortical slices were not affected by PBB. In conclusion, chronic exposure to PBB resulted in significant alterations in renal and hepatic microsomal enzyme activities but had no detectable effect on renal function. These experiments suggest that alterations in microsomal enzyme activities following PBB do not lead to impairment of renal function; however, this compound may sensitize the kidney to toxicity produced by agents administered subsequent to PBB.     

3,5-Dichloroaniline-induced nephrotoxicity in the Sprague-Dawley rat

The nephrotoxie potential of 3,5-dichloroaniline (DCA) was examined in male Sprague-Dawley rats. Rats were administered DCA (0.4, 0.8 or 1.0 mmol/kg, i.p.), or 0.9% saline (1.0 ml/kg, i.p.), and renal function was monitored at 24 and 48 h. DCA (0.4 mmol/kg) administration did not produce evidence of nephrotoxicity. However, DCA (0.8 mmol/kg) administration decreased urine volume and osmolality, increased proteinuria, elevated the blood urea nitrogen (BUN) concentration and decreased basal and lactate-stimulated p-aminohippurate (PAH) accumulation. Three of 4 rats receiving DCA (1.0 mmol/kg) died prior to 48 h postinjection. Incubation of renal cortical slices with DCA resulted in decreased PAH and tetraethylammonium (TEA) uptake when DCA concentrations of 10⁻⁶ M or greater were used. These results indicate that DCA is nephrotoxic to Sprague-Dawley rats when administered in a dose of 0.8 mmol/kg or higher and is capable of altering organic ion transport in vitro.     

Renal Protein Degradation: A Biochemical Target of Specific Nephrotoxicants

Renal Protein Degradation: A Biochemical Target of SpecificNephrotoxicants. Cojocel, C., Smith, J.H., Maita, K., Sleight,S.D. and Hook, J.B. (1983). Fundam. Appl. Toxicol. 3: 278–284.Protein degradation in the kidney occurs mainly in lysosomes,organelles which may also accumulate nephrotoxic chemicals.The goal of this study was to evaluate the effects of intracellularaccumulation of gentamicin, cephaloridine and cisplatin on lysosomaldigestion of the protein lysozyme. Gentamicin (15 or 30 mg/kg/dayfor 3 or 5 days), cisplatin (2.5 or 5 mg/kg) or cephaloridine(500, 1000, 2000 or 2500 mg/kg) was administered ip to maleWistar rats. The main site of the nephrotoxic effects of thesecompounds was the proximal tubule where these agents differentiallyaffected S₁, S₂ and/or S₃ segments. A 2- and 4-fold increaseof the excretion of N-acetyl-ß-D-glucos-aminidase(NAG) was observed in the urine from cisplatinand gentamicin-treatedrats, respectively; no change in enzyme excretion occurred aftercephaloradine. One hour prior to sacrifice, rats were given0.3 mg of unlabelled lysozyme in combination with ¹²⁵I-lysozymein 0.3 mL saline. Renal cortical slices were prepared and incubatedfor 15, 30, 60 and 90 min. Release of trichloroacetic acid (TCA)solubleradioactivity into the medium was assumed to quantify lysosomaldegradation of lysozyme. Accumulation of p-amino-hippurate (PAH)in renal cortical slices and changes in blood urea nitrogen(BUN) concentration were used as indices of renal damage. TCA-solubleradioactivity increased in the medium from kidney slices fromcontrol rats to 50% of the total radioactivity after 90 minincubation. In gentamicin treated rats, lysozyme degradationwas significantly decreased by doses of 15 and 30 mg/kg/dayafter 3 and 5 days of exposure in the absence of any changesin BUN or PAH accumulation. Increased BUN and decreased PAHaccumulation was accompanied by reduced release of lysozymedegradation products from kidney slices of rats treated withboth doses of cisplatin. Cephaloridine appeared to have no effecton renal catabolism of lysozyme at 500 and 1000 mg/kg; howeverat higher doses lysozyme degradation decreased and changes inBUN and PAH occurred. Thus, all three compounds used were effectivein decreasing renal catabolism of lysozyme. Protein degradationwas an early and sensitive indicator of aminoglycoside-inducednephrotoxicity since a decrease in protein degradation in kidneyslices from gentamicin-treated rats was not associated withalterations in BUN or PAH accumulation but was associated withultrastructural changes.     

Protection against mercuric chloride by nephrotoxic agents which do not induce thionein

Kidney damage caused by the ip administration of 1.1 mg/kg mercury given as HgCl₂ was less marked in 7-week-old male rats when mercury was given 7 days after the administration of one of the following nephrotoxic agents: 20 mg/kg sodium chromate, 100 mg/kg p-aminophenol, or 500 mg/kg sodium maleate, or 14 days after the injection of 4.0 mg/kg uranyl acetate. All four nephrotoxic agents were given in sufficient doses to cause renal damage. In the first 3–4 days after the administration of the nephrotoxic agents they increased the urinary excretion of alkaline phosphatase, glutamic oxaloacetic transaminase, and lactic dehydrogenase and caused widespread necrosis in the proximal tubular cells. In the first 24 hr after the injection of mercury, the urinary excretion of the three enzymes tested was lower in pretreated than in nonpretreated rats. Tubular cell necrosis was also less extensive in pretreated than in nonpretreated rats, and calcification could be seen 10 days after mercury only in the kidneys of the nonpretreated rats. The decreased susceptibility of regenerating kidneys to the tubulotoxic effect of mercuric chloride seems to be a general phenomenon which is unrelated to the renal concentration of metallothionein or change in renal mercury uptake.     

Toxic effect of concomitant administration of cyclosporin A and acyclovir on renal function and morphology in rats

The immunosuppressive agent cyclosporin A (CyA) and the antiviral drug acyclovir may cause renal functional impairment. CyA-induced immunosuppression increases the rate of viral infections. Therefore we were interested to determine whether short-term co-administration of CyA and acyclovir involves an increased nephrotoxic risk. Male Wistar rats were treated with CyA (20 mg/kg body wt., s.c., once daily for 8 days), acyclovir (15 mg/kg body wt., s.c., 3-times daily for the last 5 days) or a combination of CyA and acyclovir. Blood levels of CyA were determined after a single dose. Urine was monitored for volume, osmolality, total protein and N-acetyl-β-d-glucosaminidase (β-NAG). Concentrations of blood urea nitrogen (BUN) and plasma-creatinine were determined (day 9). Renal cortical slices were monitored for accumulation of weak organic acids (para-aminohippurate, PAH) and bases (tetra-ethylammonium, TEA) and for malondialdehyde (MDA) content. Renal histology was also examined. CyA induced a decrease in body and kidney weight, in urine osmolality and in the excretion of total protein. Plasma-creatinine and BUN as well as MDA content of renal tissues were increased by CyA. Acyclovir alone did not induce significant changes. In comparison to CyA values, urine volume and β-NAG excretion were enhanced and TEA accumulation depressed by the concomitant administration of CyA and acyclovir. CyA- or acyclovir-treatment alone did not result in significant morphological changes. In the group co-administered CyA/acyclovir, the kidneys showed mild to moderate signs of tubulopathy. Short-term co-administration of CyA and acyclovir was concluded to have possibly increased nephrotoxic potential. Received: 28 August 1996 / Accepted: 9 April 1997     

The effect of unilateral nephrectomy on the nephrotoxicity of mercuric chloride in the rat

Unilateral nephrectomy (UNX) induces a dramatic change in single-kidney structure and function. Therefore, the effects of nephrotoxins may be altered. To evaluate this possibility, mercuric chloride (2 mg/kg, sc) was given to male, Sprague-Dawley rats 2 days following either UNX or sham surgery. Nonoliguric acute renal failure developed and was qualitatively similar in both groups. Glomerular filtration rate (GFR) reached a nadir on Day 2 and was reduced to a greater extent in the UNX group. Furthermore, recovery of GFR was slower and occurred to a lesser extent by Day 10 in the animals subjected to UNX. Evidence of significant tubular dysfunction was present during the acute phase in both groups, as reflected by changes in the fractional excretion of sodium or lysozyme. Persistent tubular dysfunction was noted on Day 10 in both the sham and UNX groups, but the degree of dysfunction was greater in the UNX animals. The in vitro uptake of organic ions by renal cortical slices was reduced 24 hr following the injection of mercuric chloride although no difference was seen between the experimental groups. Mercury content within renal cortex was not increased in the UNX group at 1 or 3 hr but was higher 24 hr postinjection. Total urinary mercury excretion during the first day was not altered by UNX although single-kidney excretion was increased dramatically. These studies suggest that rats are more susceptible to mercuric chloride-induced nephrotoxicity 2 days following UNX. Although the mechanism(s) of this enhanced injury remains unclear, it does not appear to be completely related to an increase in renal cortical mercury content.     

A further characterization of cytembena-induced nephrotoxicity

Cytembena (cis-β-4-methoxybenzoyl-β-bromoacrylic acid, NSC-104, 801) has been tested for its anticancer activity. One complication to its use is the possibility of drug-induced nephrotoxicity. The present study was designed to characterize further the nature of the renal damage. Rats injected ip with cytembena (50 or 150 mg/kg) showed urinary protein and glucose excretion, increased urine volumes (by 50 to 150%), and decreased urine osmolalities (from approx 1500 mosm/liter to approx 500 mosm/liter). No changes in urinary pH were noted. The slice-to-medium ratios (concentration per gram of tissue per concentration per milliliter of bathing medium) for p-aminohippurate (PAH) (with and without lactate), tetraethylammonium chloride, and α-aminoisobutyric acid uptakes were depressed by pretreatment with 150 mg/kg of cytembena. In addition, tissue slice electrolyte and water distributions were disrupted. Similar effects were produced with cytembena added directly to fresh slices, with the effects on PAH transport being the most marked. Because the organic compounds studied are transported by proximal tubules, it must be concluded that cytembena does have a proximal tubular effect.     

Amelioration of mercuric chloride-induced acute renal failure by dithiothreitol

Experiments were conducted to determine if administration of the sulfhydryl reducing agent and metal chelator dithiothreitol (31 mg/kg body wt) alters the development of renal dysfunction in the first 3 hr after injection of mercuric chloride (3 mg/kg). Mercuric chloride alone resulted in elevation of urine flow rate and fractional excretion of solutes within 30 min of injection. In animals injected with dithiothreitol 60 min after mercuric chloride, urine flow rate and fractional excretion of solutes were reduced within 30 min to values intermediate between control and mercuric chloridetreated rats. Neither the injection of mercuric chloride alone nor when followed by dithiothreitol resulted in changes in mean arterial blood pressure or glomerular filtration rate. In addition, dithiothreitol did not reduce urine flow rate or fractional excretion of solutes when these parameters were elevated during extracellular fluid volume expansion. Measurement of mercury in organs of those rats injected with mercuric chloride alone or prior to dithiothreitol revealed no alteration in organ distribution. The renal cortex contained the highest concentrations of mercury, and these concentrations were comparable in both groups of rats. These studies demonstrate that dithiothreitol can ameliorate the renal toxicity of mercury and suggest that this effect is mediated through an intrarenal site of action.     

Cystine alters the renal and hepatic disposition of inorganic mercury and plasma thiol status

In the present study, we determined whether cystine can inhibit, under certain conditions, the renal tubular uptake of inorganic mercury in vivo. We co-injected (i.v.) cystine with a non-toxic dose of mercuric chloride to rats and then studied the disposition of inorganic mercury during the next 24 h. We also determined if pretreatment with cystine influences the disposition of administered inorganic mercury. Moreover, plasma thiol status was examined after the intravenous administration of cystine with or without mercuric chloride. During the initial hour after co-injection, the renal tubular uptake of mercuric ions was diminished significantly relative to that in control rats. The inhibitory effects of cystine were evident in both the renal cortex and outer stripe of the outer medulla. In contrast, the renal accumulation of mercury increased significantly between the 1st and 12th hour after co-treatment. Urinary excretion and fecal excretion of mercury were greatly elevated in the rats co-treated with cystine and mercuric chloride. Thus, when cystine and mercury are administered simultaneously, cystine can serve as an inhibitor of the renal tubular uptake of mercury during the initial hour after co-treatment. In rats pretreated with cystine, the renal uptake of inorganic mercury was enhanced significantly relative to that in rats not pretreated with cystine. This enhanced accumulation of inorganic mercury correlated with the increased circulating concentrations of the reduced cysteine and glutathione. Additionally, the present findings indicate that thiol status is an important determinant of renal and hepatic disposition, and urinary and fecal excretion, of inorganic mercury.     

7V-Acetylpenicillamine Potentiated Excretion of Methyl Mercury in Rat Bile: Influence of S-Methylcysteine

Abstract: N-acetylpenicillamine, 5 mmol/kg body weight increased biliary excretion of methyl mercury more than three fold. Upon simultaneous administration of the same dose of N-acetylpenicillamine and 2,5 mmol/kg body weight of S-methylcysteine biliary excretion of methyl mercury increased only 1.5 fold. In both cases biliary sulfhydryl concentration increased to the same extent, about 5 fold. Decreased biliary excretion of methyl mercury, as a result of liver depletion of reduced glutathione by cyclohexene oxide, could be restored by N-acetylpenicillamine. This restoration could be depressed by S-methylcysteine. The experiments undertaken indicate that N-acetylpenicillamine potentiated methyl mercury excretion occurs by a glutathione S-transferase dependent mechanism. Bile, collected after successive administration of methyl mercuric chloride, cyclohexene oxide, S-methylcysteine and N-acetylpenicillamine contained the methyl mercuric derivatives of N-acetylpenicillamine and glutathione together with other methyl mercury carrying components not present in control bile. Whether these components play any role in the mechanism of N-acetylpenicillamine potentiated methyl mercury excretion cannot be stated from the present investigation.     

N-acetylpenicillamine potentiated excretion of methyl mercury in rat bile: influence of S-methylcysteine

N-acetylpenicillamine, 5 mmol/kg body weight increased biliary excretion of methyl mercury more than three fold. Upon simultaneous administration of the same dose of N-acetylpenicillamine and 2,5 mmol/kg body weight of S-methylcysteine biliary excretion of methyl mercury increased only 1.5 fold. In both cases biliary sulfhydryl concentration increased to the same extent, about 5 fold. Decreased biliary excretion of methyl mercury, as a result of liver depletion of reduced glutathione by cyclohexene oxide, could be restored by N-acetylpenicillamine. This restoration could be depressed by S-methylcysteine. The experiments undertaken indicate that N-acetylpenicillamine potentiated methyl mercury excretion occurs by a glutathione S-transferase dependent mechanism. Bile, collected after successive administration of methyl mercuric chloride, cyclohexene oxide, S-methylcysteine and N-acetylpenicillamine contained the methyl mercuric derivatives of N-acetylpenicillamine and glutathione together with other methyl mercury carrying components not present in control bile. Whether these components play any role in the mechanism of N-acetylpenicillamine potentiated methyl mercury excretion cannot be stated from the present investigation.     

Changes in renal function in cadmium-intoxicated rats

Changes in renal function, Na+-K+-ATPase activity and PAH transport system in kidney cortex were studied in rats treated with cadmium. Subcutaneous injections of CdCl2 (2 mg Cd/kg.day) for 16 days induced a marked polyuria and a hyposthenuria. These changes were accompanied by increase in urinary protein, glucose, urea, calcium, phosphate, chloride and potassium excretions. The change in urine flow was proportional to the change in total osmotic solute excretion. Creatinine excretion and TcH2O remained unchanged. Na+ excretion was not increased, but the Na+-K+-ATPase of renal cortex was significantly inhibited. PAH uptake by renal cortical slices was markedly attenuated in Cd-treated rats. The Vmax for active PAH influx was drastically reduced, but the Km was not changed. The passive influx and efflux of PAH across the basolateral membrane and the renal tissue oxygen consumption were not apparently altered in Cd-treated animals. These results indicate that 1) the nature of Cd-induced polyuria and hyposthenuria is an osmotic diuresis induced by proximal tubular rejection of various substances, and 2) the mechanism of impaired renal PAH excretion in Cd-treated animals is a loss of organic anion carriers in proximal tubular basolateral membranes.     

Methyl mercury: acute toxicity, tissue distribution and decay profiles in the guinea pig

Acute toxicity studies with methyl mercuric chloride showed that the guinea pig was quite susceptible to methyl mercury intoxication. LD50 values were 5.5 mg Hg/kg ip and 16.5 mg Hg/kg po. One to 2 weeks after dosing, several animals began to display signs of neurotoxicity.Tissue distribution and pharmacodynamic studies with radiolabeled methyl mercuric chloride ([²⁰³Hg]CH₃HgCl) at 1 and 10 mg Hg/kg revealed that while most tissues decreased in mercury concentration from day 1 to day 7, cerebrum, cerebellum and muscle showed a delayed uptake of the alkyl mercurial. In CNS tissue the concentration of mercury decreased in the order cerebrum > cerebellum > spinal cord. Kidney and liver consistently contained the highest levels of mercury, and plasma the lowest, during the 49-day sampling period. One week after dosing the blood: brain ratios were less than 1. The tissue concentration of mercury was generally directly proportional to the dose administered; however, mercury levels in the gall bladder were significantly higher than anticipated on 5 of the 7 sacrifice days.Most of the tissues displayed a biphasic decay profile with a half-life of 2–3 days for the initial rapid phase of decline. This initial phase was followed by a slower tissue excretion rate for which the mean half-life for mercury was 15 ± 0.9 days and 15 ± 0.8 days for the low and high dose, respectively. The similarity of these values again indicates no dose-related effects.